3-piperidylidene methane derivatives

ABSTRACT

Di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidyl)-carbinol is dehydrated. Di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidinemethane is produced. The resultant di-(2-thienyl)-(N-methyl-5methoxy-3-piperidylidene)-methane is reacted with a compound of the formula R-X, wherein R is lower alkyl and X is an anionic residue of a pharmaceutically acceptable acid. A compound having the formula   WHEREIN X and R are as defined above, is produced. This compound is a potent antispasmodic.

United States: Patent 7 mi Kawazu et al.

[ B-PIPERIDYLIDENE METHANE DERIVATIVES [75] Inventors: Mltsutaka Kawazu;Takeshl Kanno; Seiichi Saito; Hajime Tamaki, all of Saitama', Japan [73]Assignee: 'Tanabe Seiyaku Co., Ltd., Osaka,

Japan [221Filedz .Juue3, 1971 21 App1.No.: 149,849

[30] Foreign Application Priority Data OTHER PUBLICATIONS Sugimoto etal., Chem. and Pharm. Bull. 8, 745-748 [451 Oct. 9., 1973 PrimaryExaminer-Henry R. Jiles Assistant Examiner-G. Thomas Todd Attorney-HarryC. Bierman and Jordan B. Bierman [57] ABSTRACTDi-(2-thienyl)-(N-methyl-5-methoxy-3-piperidyl)- carbinol is dehydrated.Di-(2-thienyl)-(N-methyl-5- methoxy-3-piperidylidine-methane isproduced. The resultant di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidene)-methane is reacted with a compound of the formula R-X,wherein R is lower alkyl and X is an anionic residue of apharmaceutically acceptable acid. A compound having the formula c: oorn5/ I I wherein X and R are as defined above, is produced. This compoundis a potent antispasmodic.

7 Claims, No Drawings l 3-PIPERIDYLIDENE METHANE DERIVATIVES Thisinvention relates to novel derivatives of di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidene)- methane and to a processfor preparing same.

The derivatives are represented by the formula:

electrical stimulation of the cervical vagus nerve inrats. Theinhibitory activity (ED' of' the compound which would suppress 50percent of said stimulationinduced gastric contractions was ug/kg, whenthe stimulation for the distal end of the cervical vagusnerve of rat wascarried out every 2 minutes at the rate of supramaximal square waves(about 1.5 V, 10 cycles/second) 1 minute after injectinga test compoundinto the femoral vein. In contrast thereto, the EDs of atropine sulfateshowed pig/kg under the same conditions as above. Moreover, whenexamined using isolated guinea pig ileum, the anti-cholinergic activity(pA of the compound was 8.37. In contrast thereto, atropine sulfateshowed 8.57. (pA was the value of negative logarisni of the molarconcentration of a test compound which caused the shift of log.2-to highconcentration in the dose response curve of methacholine) It is wellknown that the parasympatholytics show unfavorable side effects such asmydriaticand antisialogogue activity. Such side effects of the compoundof the present invention are relatively less ascompared withparasympatholytic agents of the prior art. Forinstance, the mydriaticand anti-sialogogue activity of di-(2-thienyl)-(N-methyl-S-methoxy-3-piperidylidene)- methane methylbromideis about l-/l0 to l/20 times that of atropine sulfate. The compound ofthe present lty.

Additionally, the toxicity of the compound of the present invention isrelatively low. For instance, when administered orally, the acutetoxicity (LD of di-(2- thienyl)-(N-methyl-S-methoxy-3-piperidylidene)-methane methylbromide is more than 700 mg/kg.

According to the present invention, a compound of the formula (I) can beprepared by reacting 2-thienyl magnesium halide or 2-thienyl lithium(II) with N- methyl-S-methoxy-nipecotinic acid ester of the formula:

l CH2 (III) wherein R represents an ester residue, subjecting theresultant carbinol derivative (IV) to the dehydration reaction andreacting the thus obtained piperidylidene compound (V) with a compoundof the formula: RX

(VI), wherein R and X have the same meaning as defined above;

The above mentioned reactions are shown in U.S. Pat. Nos. 2,739,968 and2,739,969 for similar compounds and can be represented by the followingchemes;

g/ Hm crno A 04; (In) I \N l l Ilia CHsO C VI fi S 1; I,

The starting compound (III) is readily obtained. For instance, an alkylester of N-methyl-S-methoxynipecotinate maybe prepared by refluxing5-bromonicotinic acid with a mixture of sodium hydroxide, copper sulfateand copper powder, treating the thus obtained S-hydroxy-nicotinic acidwith a dialkyl sulfate in nitrogen atmosphere, and then subjecting theresultant N alkyl-piperidine derivative to catalytic reduction in thepresence of Raney-nickel.

Preferredexamples of the starting compound (VI) are a lower alkyl halide(e.g., methyl iodide, methyl bromide, methyl chloride, ethyl iodide,ethyl bromide,

' invention has almost no central anti-cholinergic activethyl chloride),a lower alkyl ester of alkanesulfonic acid (e.g., methylmethanesulfonate, methyl ethanesulfonate, ethyl ethanesulfonate), alower alkyl ester of aromatic sulfonic acid (e.g., methylp-toluene'sulfonate,

.methylbenzenesulfonate, ethyl p-toluenesulfonate,

ethyl benzenesulfonate), and di-lower alkylsulfate (e.g., di'methylsulfate, diethylsulfate). The ester residue (R') includes a lower alkylradical (e.g., methyl, ethyl, propyl radical).

The preparation of the carbinol derivative (lV) can be carried out bymixing the compounds (ll) and (III) at room temperature or underrefluxing in an inert solvent. Ether, tetrahydrofuran, benzene etc., aresuitable as the reaction solvent.

The subsequent dehydration reaction may be accomplished by heating thecompound (IV) at about 60 to C in the presence of diluted mineral acid(e.g., dilu-ted hydrochloric acid, diluted sulfuric acid).Alternatively, the reaction may be carried out by refluxing the compound(IV) with an inert solvent (e.g., benzene, toluene) in the presence ofarylsulfonic acid (e.'g., toluenesulfonic acid, benzenesulfonic acid).

The quarternary ammonium compound (I) may be prepared by conventionalmanner. For instance, it is readily obtained by mixing the compounds (V)and (VI) in an inert solvent (e.g., benzene, acetone, ether) at roomtemperature. When methyl ester of alkanesulfonic acid or methyl ester ofaromatic sulfonic acid is employed as the compound (V1), it is preferredto carry out the reaction in the presence of a catalyst such as alkalimetal iodide (e.g., potassium iodide, sodium iodide).

The compound (1) thus obtained is useful as an spasmodic agents. Thiscompound is also useful for the treatment'and/or prevention of gastriculcers, and for A the control of gastric secretion. The compound may beused in the form of a pharmaceutical preparation for enteral orparenteral administration at a daily dose of 0.05 to 50 r'ng/kg.

Practical and presently-preferred embodiments of the present inventionare illustratively shown in the following Examples.

Example 1 50 g of S-bromonicotinic acid are added to a solutioncontaining 50 g of sodium hydroxide, g of copper sulfate 5 hydrate, 2 gof copper powder and 400 ml of water. The mixture is refluxed for hoursunder stirring and then cooled. Hydrogen sulfide gasis introduced intothe mixture. Then, the mixture is decolorized with activated carbon andfiltered. The filtrate is adjusted to pH 3 4 with hydrochloric acid. Theprecipitated crystals are collected by filtration. Recrystallization ofthe crystals from methanol gives g of 5- hydroxynicotinic acid. M.P. 298299 C (decomp.)

120 g of S-hydroxynicotinic acid are dissolved in one liter of methanol.After saturating with dry-hydrogen chloride gas at 0 C, the solution isrefluxed for 2 hours. Then, the solution is concentrated to dryness. Theresidue thus obtained is dissolved in water. The solution is alkalifiedwith sodium bicarbonate. The precipitated crystals are collected byfiltration, washed with water and then dried. 126 g of methylS-hydroxy-nicotinate are obtained. Yield; 93 M.P. 184 186 C 460 g ofmethyl S-hydroxynicotinate and 621 g of potassium carbonate aresuspended in 200 ml of tetrahydrofuran-methanol (4:1). 1,134 g ofdimethylsulfate are added dropwise to the suspension in nitrogenatmosphere at room temperature. The mixture is stirred overnight at thesame temperature and then filtered. The filtrate is concentrated todryness. The residue thus obtained is mixed with 1.6 liters of methanoland 280 ml of Raney-nickel, and hydrogenated overnight in an autoclaveat room temperature and at a pressure of 85 atmospheres. 200 g ofRaney-nickel are added to the reaction mixture. The mixture is adjustedto pH 9.5 with triethylamine, and is further subjected to hydrogenationfor 20 hours in an autoclave at 70 C and ata g of magnesium and 80 ml oftetrahydrofuran under stirring at C. The mixture is stirred'for 5 hoursat room temperature until the magnesium is entirely dissolved in thesolution. 6.2 g of methyl N-methyl-S- methoxy-nipecotinate are added tothe mixture. Then,

the mixture is refluxed for 4 hours. After the reaction is completed,tetrahydrofuran is distilled off under reduced pressure. An aqueousammonium chloride solution is added to the residue, and the solution isextractd with chloroform. The extract is dried and then evaporated toremove chloroform. The viscous oil thus obtained is recrystallized froma mixture of benzene and ether. 7 g of di-(2-thienyl)-(N-methyl-5-methoxy-3- piperidyl)-carbinol are obtained ascrystals. M.p. 142 146 C.

7 g of the product are dissolved in 150 ml of 10 hydrochloric acid, andthe solution is heated at 80 C for 30 minutes. After the reaction iscompleted, the solution is alkalified with sodium hydroxide and thenextracted with ether. The extract is washed with water, dried andevaporated to remove ether. 5 g of di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidene)- methane are obtained aspale yellow oil.

Infrared absorption spectrum:

NTMR. mo) (in CDCl;,):

365 mg of .di-(2-thienyl)-(N-methyl-5-methoxy-3- piperidylidene)-methaneare dissolved in 15 ml of ether. One ml of methyl bromide is added tothe solution. Then, the solution is stirred overnight. The precipitatedcrystals are collected by filtration and recrystallized from a mixtureof acetone and ether. 390 mg of di-(2-thienyl)-(N-methyl-S-methoxy-3-piperidylidene)- methane methylbromideare obtained as colorless crys tals. M.p. 198 200 C.

Infrared absorption spectrum:

riff cm": 1,460, l,378, 1,100, 834, 800, 715, 700 Example 2 A solutionof Z-thienyl lithium in 200 ml of ether is prepared from 1.4 g of metallithium and 18 g of 2- thienyl bromide by conventional manner. 4 g ofmethyl N-methyl-S-methoxy-nipecotinate are added dropwise to thesolution. The solution is refluxed for 8 hours and then allowed to standatroom temperature. The solution is evaporated to remove ether.Ice-water is added to the residue, and the mixture is extracted withchloro- C for 2 hours. After cooling, the solution is alkalipressure ofatmospheres. Potassium carbonate and,

a small amount of ice are added to the reaction mixture to bring the pHto 11. The mixture is extracted with ether. After drying, the etherlayer is filtered. The filtrate is evaporated to remove ether. Theresidue thus obtained is distilled under reduced pressure. 450 g of fiedwith sodium hydroxide 'to pH 9.0 and then extracted with benzene. Theextract is dried and evaporated to remove benzene. The residue thusobtained is purified by distillation and then suspended in ether. Theprecipitated crystals are collected by filtration. 64 g ofdi-(Z-thienyl) -(N-methyl-5-methoxy-3- piperidylidene)-methane areobtained as colorless crystals. M.p. 70 71 C.

500 mg of di-(2-thienyl)-(N-methyl-5-methoxy-3- piperidylidene)-methaneare dissolved in 10 ml of acetone. A solution of 1.25 g of ethyl iodidein 10 ml of acetone is added to the solution under stirring at roomtemperature, and the mixture is stirred ovemight. Then, the mixture isevaporated to remove solvent. The

residue thus obtained is recrystallizedfrom a mixture of acetone,methanol and isopropanol. 650 mg of di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidene)- methane ethyl iodide areobtained as pale yellow crystals. Recrystallization of the crystalsgives colorless granular crystals. M.p. 201 202 C.

Infrared absorption spectrum: #1122 cm": 1,460, 1,450, 1,370, 1,093,1,065, 1,013,

8 28, 750, 700 What we claim is: l. A compound represented by theformula:

" is ethyl.

5. The compound as claimed in claim 1 wherein X is a halide,p-toluenesulfonate, benzenesulfonate, methylsulfonate or ethylsulfonateion.

.6. The compound as claimed in claim 1, wherein X is a halide ion.

7. The compound as claimed in claim 1, wherein X is a chloride, bromideor iodide ion.

2. Di-(2-thienyl)-(N-methyl-5-methoxy-3-piperidylidene)-methane.
 3. Thecompound as claimed in claim 1, wherein R is methyl.
 4. The compound asclaimed in claim 1, wherein R is ethyl.
 5. The compound as claimed inclaim 1, wherein X is a halide, p-toluenesulfonate, benzenesulfonate,methylsulfonate or ethylsulfonate ion.
 6. The compound as claimed inclaim 1, wherein X is a halide ion.
 7. The compound as claimed in claim1, wherein X is a chloride, bromide or iodide ion.